PROJECT ABSTRACT Urinary dysfunction is among the most widespread disorders affecting aging men. Despite an annual treatment burden of over four billion dollars, therapies for this dysfunction remain based on the decades-old observation that prostate size often predicts symptoms. As a result, current treatments are effective for less than 40% of patients. To fully understand the complex etiology of this disease, we will investigate how perinatal exposure to an environmental contaminant impacts adult urinary health, a completely new direction for urologic research. Our preliminary results show that in utero and lactational (IUL) exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) causes increased susceptibility to urinary dysfunction in mice. TCDD is a widespread contaminant, ubiquitous in serum of American men, and a selective activator of the aryl hydrocarbon receptor, a receptor that can be activated by many persistent organic pollutants. Through histological analysis of prostate tissue from mice given IUL TCDD, we identified a possible mechanism for potentiation of urinary dysfunction: systemic changes to prostatic stroma and extracellular matrix elements, namely prostate fibrosis. A similar mechanism may mediate prostate changes in aging men, in which prostate collagen content and stiffness have been found to associate with dysfunction. These results present unique opportunities to link adult urinary dysfunction to early- life chemical exposure and clearly define the contributions of prostate fibrosis to urinary dysfunction. Using a novel combination of genetic mouse strains, chemical exposures, and computational tools, this proposal?s specific aim will test whether prostate fibrosis is sufficient to drive urinary dysfunction in mice and if anti-fibrotic drug therapy will block the effects of prostate fibrosis on urinary function. There exists a clear link between TCDD exposure, collagen composition, and urinary dysfunction, however research in this area has moved forward without foundational evidence definitively linking these phenomena. The developmental origins of adult urinary function have never been investigated and prostate fibrosis has not been fully established as causative for dysfunction. These studies will lay the groundwork needed to support these new arms of urologic toxicology research by identifying the source and types of collagen expressed in the prostate, revealing that prostate fibrosis is sufficient to drive urinary dysfunction, and mechanistically linking early-life TCDD exposure and urinary dysfunction.